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Chapter 1. Lung Growth and Development Free To View

Hugh O'Brodovich, MD
DOI: 10.1378/ppmbr.1st.001
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Objectives 
  • Provide a brief, high-level overview of the changes in the respiratory system during fetal life

  • Provide a brief, high-level overview of the changes in the respiratory system during the perinatal period

  • Provide a brief, high-level overview of the changes in the respiratory system during the postnatal period

Lung development has been divided into various stages with names that reflect the respective histologic appearance of the lung, the region of the lung that is most obviously developing, or both. As is the case with all developmental profiles, each individual embryo or fetus will develop along its own timelines. If you consult the literature you will note different ranges being given for different stages of lung development or that there is “overlap” between the different stages. The stages of human fetal lung development are as follows:

  • Embryonic (approximately 3 to 6 weeks gestational age):

    • ̊ The lung first appears as a ventral outpouching of the primitive gut. The primary bronchi elongate into the mesenchyme and divide into the two main bronchi.

    • ̊ The main pulmonary artery arises from the sixth branchial arch.

    • ̊ Congenital abnormalities of the lung may occur during this stage (eg, lung agenesis, tracheobronchial fistula).

  • Pseudoglandular (approximately 6 to 16 weeks gestational age):

    • ̊ Branching continues, and the mesenchyme differentiates into cartilage, smooth muscle, and connective tissue around the epithelial tubes. By the end of the pseudoglandular period, all the major conducting airways, including the terminal bronchioles, have formed.

    • ̊ Arteries are evident alongside the conducting airways. By the end of the pseudoglandular period, all preacinar arterial branches have formed.

    • ̊ Congenital abnormalities of the lung may occur during this stage (eg, bronchopulmonary sequestration, cystic adenomatoid malformation, congenital diaphragmatic hernia).

  • Canalicular (approximately 16 to 26 weeks gestational age):

    • ̊ Respiratory bronchioles develop, and each ends in a terminal sac (or saccule). The glandular appearance is lost as the interstitium has less connective tissue.

    • ̊ The lung develops a rich vascular supply that is closely associated with the respiratory bronchioles.

  • Saccular (approximately 23 to 36 weeks gestational age):

    • ̊ Elastic fibers, which will be important in subsequent true alveolar development, are beginning to be laid down. At this time, cuboidal (type II alveolar epithelial [ATII]) cells and thin (type I) epithelial cells begin to line the airspace.

    • ̊ Capillary proliferation and thinning of the epithelium permit close contact between the airspace and the bloodstream, thus enabling gas exchange.

  • Alveolar period (approximately 36 weeks gestational age to a minimum of 2 years of age):

    • ̊ Secondary septae form on the walls of the saccules and grow into the lumen, forming the walls of true alveoli.

As indicated above, congenital abnormalities of the lung may occur during the various stages of development.1 In addition, factors such as oligohydramnios or decreased fetal breathing may interfere with development of the distal lung unit, including the development of alveoli. In contrast, if there is obstruction to the outflow of tracheal fluid, as occurs in laryngeal atresia, then pulmonary hyperplasia is present.

Inductive interactions, either paracrine or autocrine, between epithelium and mesenchyme cells are critical for patterning of the mammalian lung. Branching morphogenesis takes place in response to various signals. These signals are mediated by a variety of molecules, including transcription factors (eg, sonic hedgehog), secreted signaling molecules that regulate cell-to-cell interactions (eg, Wnt proteins), growth factors (eg, fibroblast growth factors), and polypeptides (eg, bone morphogenic protein-4, which is a member of the transforming growth factor–β superfamily of proteins).2 Recent work has demonstrated that the branching pattern of the developing airways of fetal lungs is remarkably stereotyped and involves three geometrically distinct local modes of branching coupled in three different sequences.3 Although the larger airways likely instruct the formation of the larger pulmonary vessels, current evidence suggests that it is the development of capillaries that guides the formation of alveoli.

Pulmonary surfactant is synthesized and secreted by the mature ATII cells. Although these cells first appear during the saccular stage, they are immature and contain much intracellular glycogen. Many drugs and hormones, including steroids and thyroid and peptide hormones, can influence surfactant biosynthesis and accelerate the maturation of surfactant synthetic capacity. Surfactant is composed of phospholipids, neutral lipids, and proteins (surfactant protein [SP]-A, SP-B, SP-C, and SP-D). Both SP-A and SP-D are hydrophilic; their most important role is to be part of the innate immune system. The hydrophobic SP-B and SP-C help lower the surface tension at the air—liquid interface by enhancing the spreading, adsorption, and stability of surfactant lipids required for the reduction of surface tension in the airspace.

At birth, the release of surfactant from ATII cells greatly increases the amount of surfactant in the alveolar space. If there is an inadequate amount or abnormal types of surfactant, then surface tension is increased, leading to reductions in endexpiratory volume and the induction of respiratory distress syndrome. Mutations in either the SP-B or SP-C surfactant genes are associated with significant clinical disease. For example, severe respiratory distress syndrome is seen with mutations in either the SP-B or SP-C genes. SP-C deficiency can also be associated with alveolar proteinosis or familial interstitial pulmonary disease.1

Distention of the lungs' airspaces by fetal lung liquid is essential for normal lung development. This fluid is neither a mere ultrafiltrate of plasma nor aspirated amniotic fluid. Rather it is generated by the active secretion of chloride by the epithelium into the developing lung's lumen, with sodium and water following passively. An inadequate amount of fetal lung liquid is associated with lung hypoplasia.

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The Perinatal Period

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Fetal Lung Liquid

At birth, the fluid within the airspace must be cleared. Thus, fetal lung liquid secretion must either decrease greatly or cease entirely. Although a vaginal delivery can result in approximately one third of the fluid being squeezed out of the lungs, the majority of fluid is cleared by the active transport of sodium by the distal lung epithelium. In infants born by Cesarean section, all fluid must be cleared by active sodium transport, with chloride and water following passively. Clearance of fetal lung liquid from the newborn's airspaces takes many hours.

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Pulmonary Vasculature

During fetal life, the pulmonary circulation receives only about 5% of the combined ventricular output. This occurs because the large amount of pulmonary arterial smooth muscle is vasoconstricted so that the combined ventricular output preferentially flows into the systemic circulation, which includes the placenta which has a very low resistance to blood flow. The physiologically normal high fetal pulmonary arterial resistance and low systemic arterial resistance also result in a large right to left shunt via the ductus arteriosus and foramen ovale. After birth the pulmonary vasculature becomes a low-resistance and low-pressure vascular bed that leads to an approximately 20-fold increase in blood flow to the lungs. The lowering of pulmonary vascular resistance occurs because of vasodilation in response to increased Pao2, the release of mediators (eg, nitric oxide, bradykinin), and clearance of airspace fluid, which causes mechanical compressive forces on the vessels.

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Ventilation

At birth the combination of thermal, tactile, and chemical (gas tensions and pH) factors stimulate a regular pattern of breathing, which contrasts to the intermittent pattern that was present during fetal life. In the immediate postnatal period and during early infancy, the vocal cords are adducted during expiration so that end-expiratory volume is kept above the “mechanical” functional residual capacity.

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Changes in Lung Function After Birth

Postnatal lung growth continues into the adolescent years. The tracheal diameter approximately triples, alveolar dimensions increase about fourfold, and alveolar numbers increase about 10-fold while body mass increases about 20-fold. The internal surface area of the lung parallels that of body mass (approximately 1 to 1.5 m2/kg of body weight). Throughout life the average values of lung lobe weight expressed as a percentage of total lung weight are approximately as follows: right upper lobe, 20%; right middle lobe, 8%; right lower lobe, 25%; left upper lobe, 22%; and left lower lobe, 25%.

Most postnatal lung growth involves the terminal respiratory unit. New secondary septae continue to appear on the walls of the saccules and grow into the airspace, thus creating more true alveoli. Alveoli continue to increase in number through segmentation of these primitive alveoli and transformation of terminal bronchioles into respiratory bronchioles, a process known as alveolarization. The number of alveoli increases rapidly from 20 million to 200 million by the third year of life, but then alveolar multiplication slows. There is no agreement as to when alveolar multiplication ceases altogether (estimates range from 2 to 8 years), but few if any new alveoli develop after 8 years of age. Further growth of the airspace then occurs through increases in alveolar dimensions. In the mature adult lung, the number of alveoli ranges from 200 million to 600 million, and an individual alveolus measures 250 to 350 μm in diameter. As alveolar multiplication occurs new blood vessels appear within the acinus. This explains the commensurate increase in the single breath diffusing capacity for carbon monoxide as the lungs grow.

The ratio of arteries to alveoli increases throughout childhood. The alveolar/arterial ratio is 20:1 in the newborn, 12:1 in a 2-year-old child, and 8 to 10:1 in an older child. The muscularization of the arteries lags during childhood, with a return to muscularization of more peripheral arteries by adult life. Healthy children grow along their lung function growth curve, much like children grow along their own height curve. For example, healthy child who is born with lung volumes at the 10th percentile will usually maintain that status throughout childhood.

Postnatal lung growth can be either impaired by restriction of the lung (eg, in kyphoscoliosis) or augmented (eg, in remaining lung post-pneumonectomy). Lung capacities and flows continue to increase until late adolescence. As adults, nonsmoking men and women have an annual decline in their FEV1 of approximately 20 mL/year.4 The rate of decline during adult life is increased when individuals smoke or have a history of repeated childhood respiratory disorders.

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Financial/nonfinancial disclosures

The author has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this chapter.

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References

Whitsett JA, Wert SE, Trapnell BC.  Genetic disorders influencing lung formation and function at birth.  Hum Mol Genet.  2004;13(Spec No 2):R207–-R215. . [PubMed] [CrossRef]
 
Shu W, Jiang YQ, Lu MM, Morrisey EE.  Wnt7b regulates mesenchymal proliferation and vascular development in the lung.  Development.  2002;129(20):4831–-4842. . [PubMed]
 
Metzger RJ, Klein OD, Martin GR, Krasnow MA.  The branching programme of mouse lung development.  Nature.  2008;453(7196):745–-750. . [PubMed] [CrossRef]
 
Kohansal R, Martinez-Camblor P, Agusti A, Buist AS, Mannino DM, Soriano JB.  The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort.  Am J Respir Crit Care Med. 2009;180(1):3–-10. . [PubMed] [CrossRef]
 

References

Whitsett JA, Wert SE, Trapnell BC.  Genetic disorders influencing lung formation and function at birth.  Hum Mol Genet.  2004;13(Spec No 2):R207–-R215. . [PubMed] [CrossRef]
 
Shu W, Jiang YQ, Lu MM, Morrisey EE.  Wnt7b regulates mesenchymal proliferation and vascular development in the lung.  Development.  2002;129(20):4831–-4842. . [PubMed]
 
Metzger RJ, Klein OD, Martin GR, Krasnow MA.  The branching programme of mouse lung development.  Nature.  2008;453(7196):745–-750. . [PubMed] [CrossRef]
 
Kohansal R, Martinez-Camblor P, Agusti A, Buist AS, Mannino DM, Soriano JB.  The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort.  Am J Respir Crit Care Med. 2009;180(1):3–-10. . [PubMed] [CrossRef]
 
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